Currently, sustained release systems are widely applied in various therapies, including surgical transplant, tissue regeneration or wound wrap therapies. Generally, drugs or bioactive substances are delivered to specific sites to cure various diseases using the sustained release systems. Specifically, the sustained release systems may deliver antibiotics to a specific site to prevent other sites from infection or combine with tissue regeneration engineering to provide essential growth factors.
Thus, development of safe sustained release systems with improved functions is desirable. For example, a sustained release system may be capable of generating high drug activity with minimal side effect. Biodegradable materials have been widely applied in sustained release systems because of their stable release rates and lack of toxicity. Common drugs used in sustained release systems include small molecules, peptides or proteins.
Common biodegradable materials are aliphatic polyesters include polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polyanhydride or polycaprolactone (PCL). Such biodegradable materials can be shaped into various shapes. Specifically, for example, sponge, strip, fiber, colloid or microparticle (micrograin) shapes. As those skilled in the art know, the shape of a biodegradable material affects the physical properties of carried drugs when applied by an intramuscular injection or a subcutaneous injection. Biodegradable materials with microparticle shapes are popularly used because of their characteristics include: small size of about 0.1 to 500 μm, controlled release rate and their facilitation to inject directly to an organism. Thus, development of microparticle with small size and high entrapment efficiency is desirable.
Currently, processes for forming microparticles comprise emulsion solvent evaporation, phase separation, spray-drying, solvent extraction, atomization-freeze, salting out or nano-precipitation processes. For emulsion solvent evaporation, a hydrophobic polymer is dissolved in an organic solvent includes dichloromethane, chloroform or ethyl acetate, to form a polymer solution. A hydrophobic drug is then dissolved and suspended in the polymer solution. Second, the polymer solution is added to an aqueous solution containing a hydrophilic surfactant. After removal of solvent, a micrograined sustained release system is obtained. Even though the method of emulsion solvent evaporation is suitable for the use of hydrophobic drugs, it can not be applied to hydrophilic drugs.
The double emulsion method of water-in-oil-in-water (w/o/w) is suitable for the use of hydrophilic drugs. A biodegradable material and a hydrophobic surfactant are dissolved in an organic solvent to prepare a polymer solution. A hydrophilic drug solution is then emulsified with the polymer solution to form a w/o emulsion. The w/o emulsion is emulsified with an aqueous solution contains a hydrophilic surfactant to form a w/o/w double emulsion system. After removal of solvent, a micrograined sustained release system encapsulating hydrophilic drugs is obtained.
Additionally, a solid-in-oil-in-water (s/o/w) emulsion method has also been developed. A protein drug is lyophilized to form a solid. The solid protein drug is then encapsulated by the s/o/w phase. However, the activity of the protein drug will be decreased during the process of lyophilization because it is exposed in an organic solvent and has no protection. Also, the solid protein drug often does not uniformly disperse in the organic solvent with the s/o/w emulsion.
Thus, development of a preparation method or composition capable of protecting and effectively carrying a sensitive drug is desirable, particularly for susceptible hydrophilic drugs. The susceptible hydrophilic drugs include peptides, proteins or nucleic acid. However, when some biodegradable materials are hydrolyzed in an organism, its microenvironment pH value may be reduced, deteriorating cell growth. Thus, development of a sustained release system capable of protecting a drug, sustained release and effectively carrying drugs is essential.
Calcium phosphate ceramics such as hydroxyapatite and β-tricalcium phosphate (β-TCP) are used as bone substitute materials in the repair of bone defects. In particular, β-TCP is widely used in clinical orthopedic surgery due to its high osteoconductivity, easy manipulation, and a lack of histotoxicity. U.S. 6344209 disclosed a solid composition comprising a medicinal substance and an apatite-coated biodegradable polymer. It also disclosed a method for producing this solid composition by subjecting a substrate comprising a medicinal substance and a biodegradable polymer to immersion in an aqueous ion solution which is capable of forming an apatite. U.S. Patent Application 20090087472 relates to controlled release of biopharmaceutical growth factors from a hydroxyapatite coating on a bioresorbable substate used in orthopedic implant.